Sex differences in DNA damage response

DNA损伤反应的性别差异

基本信息

  • 批准号:
    10435628
  • 负责人:
  • 金额:
    $ 18.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-18 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Abstract: The sex of an individual has been associated with the frequency of various health conditions, responses to disease treatment, incidence of drug-associated toxicities, and lifespan. The current literature remains unclear and conflicting with regard to sex-dependent differences in DNA damage response, especially as it relates to DNA damaging agents, such as radiation therapy (RT) which is an indicated treatment in more than half of newly diagnosed cancers. Thus, pharmacodynamic (PD) biomarkers based on assessment of DNA damage endpoints may prove valuable not only in translational and clinical cancer research but in standard RT practices. Presently, there is a lack of robust validated PD biomarkers that can quantify cellular responses to DNA damage. Ataxia telangiectasia mutated kinase (ATM) is activated by DNA double-strand breaks (DSBs) through intermolecular autophosphorylation on serine-1981. ATM serine-1981 phosphorylation (p-ATM) is increased >50% in cells exposed to as little as 5 cGy γ-rays. This sensitivity/stoichiometry suggest that p-ATM may be an appropriate and reliable PD biomarker of radiation-induced DNA damage. Thus, we developed a fit-for-purpose quantitative multiplexed assay to analyze p-ATM and pan ATM protein. This assay documented the first reported induction of p-ATM in patient PBMCs following radiation therapy or chemotherapy. To address sex differences in ATM activation, we obtained PBMCs from male and female volunteers and measured the normal basal levels of ATM as well as the ATM activation following ex vivo irradiation. PBMCs isolated from women have a 2.6-fold greater induction of p-S1981-ATM expression than men following exposure to 2 Gy IR. It is therefore likely that RT-induced p-ATM will differ between male and female patients and that this difference may manifest as different responses and/or toxicities in the clinical setting. We hypothesize that ATM phosphorylation at serine-1981 is a sensitive PD biomarker of DNA damage response capable of defining sex differences and RT toxicities. To address this hypothesis, we propose two specific aims in this application. Aim 1 will quantify DNA damage signaling and repair in PBMCs from male and female cancer patients receiving RT. Aim 2 will evaluate and quantify DNA damage signaling in sorted PBMCs obtained from normal subjects following ex vivo DNA damage to identify specific immune cell populations most induced by radiation. Completion of these Aims will validate p-ATM as a biomarker of DNA damage and repair in patients receiving RT and advance p-ATM as a biomarker of radiation toxicity that may allow dose reduction such that patients experiencing toxicity can complete their therapy.
摘要: 个体的性别与各种健康状况、反应 与疾病治疗、药物相关毒性的发生率和寿命有关。当代文学 关于性别依赖的DNA损伤反应的差异,仍然不清楚和相互矛盾, 尤其是当它与DNA损伤剂有关时,如放射治疗(RT),这是一种指示 在新诊断的癌症中,有超过一半的人在接受治疗。因此,药效学(PD)生物标志物 根据对DNA损伤的评估,终端可能被证明不仅在翻译和 临床癌症研究,但在标准的RT实践中。目前,缺乏健壮的验证PD 可以量化细胞对DNA损伤的反应的生物标志物。共济失调毛细血管扩张症突变激酶 (ATM)是由DNA双链断裂(DSB)通过分子间自动磷酸化激活的 在丝氨酸上-1981年。染砷细胞中ATM丝氨酸-1981磷酸化(p-ATM)增加50% 小至5cGy型γ射线。这种敏感性/化学计量学表明,p-ATM可能是一种合适的 辐射诱导DNA损伤的可靠PD生物标志物。因此,我们开发了一种适用于特定用途的 P-ATM和PAN ATM蛋白的定量多重分析。这项化验记录了 首次报道了放射治疗或化疗后患者PBMC中p-ATM的诱导。至 为了解决ATM激活过程中的性别差异,我们从男性和女性志愿者和 测定正常基础水平及体外照射后ATM的激活情况。 从女性分离的PBMC诱导p-S1981-ATM表达的能力是男性的2.6倍 照射2GyIR后。因此,RT诱导的p-ATM很可能在男性和 这种差异可能表现为不同的反应和/或毒性 临床环境。我们假设ATM丝氨酸-1981位的磷酸化是一个敏感的PD生物标志物 能够确定性别差异和RT毒性的DNA损伤反应。要解决这个问题 假设,我们在这一应用中提出了两个具体的目标。目标1将量化DNA损伤信号 接受放射治疗的男性和女性癌症患者的外周血单核细胞修复。目标2将评估和 用体外DNA定量检测正常人分选PBMCs中的DNA损伤信号 损伤以识别最受辐射诱导的特定免疫细胞群。完成这些工作 AIMS将验证p-ATM作为接受放疗和治疗的患者DNA损伤和修复的生物标志物 先进的p-ATM作为辐射毒性的生物标志物,可能允许减少剂量,使患者 经历毒性可以完成他们的治疗。

项目成果

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JOHN C SCHMITZ其他文献

JOHN C SCHMITZ的其他文献

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{{ truncateString('JOHN C SCHMITZ', 18)}}的其他基金

Sex differences in DNA damage response
DNA损伤反应的性别差异
  • 批准号:
    10610901
  • 财政年份:
    2022
  • 资助金额:
    $ 18.51万
  • 项目类别:

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